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Ng, Felicity Wai-Yan; Berk, Michael; Dean, Olivia; Bush, Ashley I. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications International Journal of Neuropsychopharmacology, 2008; 11(6):851-876

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Oxidative stress in psychiatric disorders:evidence base and therapeutic implications

Felicity Ng1, Michael Berk1,2,3, Olivia Dean2 and Ashley I. Bush2

1 Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, Geelong, VIC, Australia2 Mental Health Research Institute of Victoria, Parkville, VIC, Australia3 ORYGEN Research Centre, Parkville, VIC, Australia

Abstract

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common

pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively

greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of

oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search

was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane

databases, with a time-frame extending to September 2007. The broadest data for oxidative stress

mechanisms have been derived from studies conducted in schizophrenia, where evidence is available

from different areas of oxidative research, including oxidative marker assays, psychopharmacology

studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for

oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical

therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly

supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of

N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms

in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support

the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative

mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also intro-

duce new targets for the development of therapeutic interventions.

Received 15 October 2007; Reviewed 12 November 2007; Revised 4 December 2007; Accepted 10 December 2007;

First published online 21 January 2008

Key words : Antioxidant, mechanisms, oxidative stress, pathophysiology, psychiatric disorders.

Introduction

The aetiopathogenesis of psychiatric disorders is in-

completely understood, which may partly account for

the persisting dominance of the syndromic nosology

in psychiatry, despite its widely recognized inad-

equacies. An obstacle to the furthering of aetiological

understanding is the complex interplay of multitud-

inous variables, such that the precise delineation of

aetiology may be an unattainable goal. In this context,

a better understanding of fundamental pathophysio-

logical pathways and their interactions may provide a

broadly applicable conceptual framework and sub-

sequent means of therapeutic intervention. Biomedical

fields such as neurochemistry, psychoneuroendo-

crinology and psychoneuroimmunology are major

contributors in this respect, and neurochemistry, in

particular, informs most of the current biological treat-

ments. In a similar vein, oxidation biology is emerging

as a promising avenue of investigation, and has been

actively pursued in other areas of medicine (Barnham

et al., 2004; Mehta et al., 2006; Tsukahara, 2007).

The theory of oxidative stress as a pathophysio-

logical mechanism, at its most basic, can be explained

by the concept, sometimes referred to as the ‘oxygen

paradox’, that while oxygen is essential for aerobic

life, excessive amounts of its free radical metabolic

by-products are toxic (Davies, 1995). In brief, these

free radicals play integral roles in cellular signalling,

physiological immunological responses and mitosis.

However, being highly unstable molecules with un-

paired electrons, they have differential oxidative

strengths and hence potential to damage cellular pro-

teins, lipids, carbohydrates and nucleic acids (Filomeni

Author for correspondence: Dr F. Ng, Swanston Centre, PO Box 281,

Geelong, VIC 3220, Australia.

Tel. : +61 3 5260 3154 Fax : +61 3 5246 5165

E-mail : [email protected]

International Journal of Neuropsychopharmacology (2008), 11, 851–876. Copyright f 2008 CINPdoi:10.1017/S1461145707008401

REVIEW ARTICLE

CINP

and Ciriolo, 2006). Under physiological conditions,

multiple tiers of defence exist to protect against these

free radicals, including the restriction of their pro-

duction through the maintenance of a high oxygen

gradient between the ambient and cellular environ-

ments, their removal by non-enzymatic and enzymatic

antioxidants, and the reparation of oxidative damages

by structural repair and replacement mechanisms

(Davies, 2000; Sies, 1997). Despite the efficiency of this

multi-faceted defence network, a degree of oxidative

damage is inherent in aerobic life and is believed to

underlie the ageing process and influence organismic

lifespan (Finkel and Holbrook, 2000). Oxidative stress

occurs when redox homeostasis is tipped towards an

overbalance of free radicals, due to either their over-

production or deficiencies in antioxidant defence (Sies,

1997). The resultant cellular damage may range from

cellular structural damage and mitotic arrest, to

apoptosis and cell necrosis, depending on the level of

oxidative stress severity (Davies, 2000; Finkel and

Holbrook, 2000). The major classes of free radicals in

living organisms are the reactive oxygen species (ROS)

and the reactive nitrogen species (RNS), which are

respective collective terms for oxygen- and nitrogen-

derived radicals, as well as some non-radicals that

readily convert into radicals (Halliwell, 2006; Pacher

et al., 2007).

Oxidative stress mechanisms have been implicated

in the pathogenesis of psychiatric disorders. This hy-

pothesis has theoretical appeal, as the brain is con-

sidered particularly vulnerable to oxidative damage

for several reasons. These include its comparatively

high oxygen utilization and hence generation of free

radical by-products, its modest antioxidant defences,

its lipid-rich constitution that provides ready sub-

strates for oxidation, the reducing potential of certain

neurotransmitters, and the presence of redox-catalytic

metals such as iron and copper (Halliwell, 2006; Valko

et al., 2007). Additionally, the brain is also susceptible

to secondary and self-perpetuating damage from oxi-

dative cellular injury or necrosis, via the neurotoxic

effects of released excitatory amines (mainly gluta-

mate) and iron, and the activated inflammatory

response (Halliwell, 2006). This intrinsic oxidative

vulnerability of the brain, together with the growing

evidence for neurodegenerative changes associated

with many psychiatric syndromes, suggest that oxi-

dative damage may be a plausible pathogenic candi-

date.

The focus of this review is on examining the evi-

dence for oxidative stress involvement in psychiatric

pathophysiology, and to comment on the therapeutic

and research implications of this knowledge.

Methods

A literature search was conducted using the Medline,

Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Pre-

views, and Cochrane databases, up until September

2007. Search terms entered included: ‘oxidative, oxi-

dative stress, reactive species, reactive oxygen species,

reactive nitrogen species, antioxidants, lipid peroxi-

dation, thiobarbituric acid reactive substances, DNA

damage, psychiatry, pathogenesis, mental disorder,

schizophrenia, bipolar disorder, depression, anxiety

disorder, personality disorder, autism, attention deficit

hyperactivity disorder, glutathione, N-acetylcysteine,

and treatment’, grouped in various combinations.

This was supplemented by a hand search of references

in selected articles, as well as references obtained from

researchers of oxidative mechanisms in the field of

psychiatry. Some references from this latter source

have been published after the initial search date of

September 2007.

Results

Over the last decade, there has been a proliferation of

information on oxidative stress mechanisms in the

psychiatric literature (Figure 1). The largest and most

multi-faceted body of research exists for schizo-

phrenia, followed by bipolar disorder and depression.

A smaller collection of data has been published for

anxiety disorders, substance abuse, autism and atten-

tion deficit hyperactivity disorder (ADHD). No studies

were found for personality disorder, and the search

did not yield oxidative stress literature pertaining to

other psychiatric conditions.

0

5

10

15

20

25

30

35

2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996

Year

Nu

mb

er o

f p

ub

licat

ion

s

Figure 1. Estimated number of original research publications

on oxidation biology in core psychiatric disorders

(schizophrenia, bipolar disorder, major depressive

disorder, anxiety disorders) by year, as gauged by Medline

database search.

852 F. Ng et al.

Schizophrenia

The evidence behind oxidative stress mechanisms in

schizophrenia can be grouped into three categories:

first, those studies that illustrate disturbed oxidative

homeostasis through oxidative enzyme genetic poly-

morphism and quantification of antioxidants, free

radicals and markers of oxidative damage; second,

those demonstrating antioxidant mechanisms of es-

tablished antipsychotic drugs; third, those showing

benefits from antioxidant therapies. These findings are

summarized in Table 1.

Markers of oxidative disturbances

Assays of oxidants and antioxidants

Most data demonstrating oxidative disturbances have

examined indirect measures of oxidative status, such

as peripheral and brain levels of antioxidants, oxidat-

ive enzymes and products. The direct measurement of

free radicals is hindered by their short half-lives and

low titres. Some studies have examined peripheral

concentrations of the free radical nitric oxide (NO)

in patients with schizophrenia by measuring its meta-

bolites, nitrites and nitrates, but have yielded incon-

sistent results. Whilst some have found elevated

plasma NO (Akyol et al., 2002; Li et al., 2006; Taneli

et al., 2004; Yanik et al., 2003; Zoroglu et al., 2002)

and reduced polymorphonucleocyte NO (Srivastava

et al., 2001) in those with schizophrenia compared

with controls, no significant changes were found in

plasma and platelet NO (Srivastava et al., 2001).

Comparatively lower concentrations of the NO meta-

bolites were found in the cerebrospinal fluid (CSF)

of schizophrenia patients (Ramirez et al., 2004) com-

pared with control patients who presented with non-

inflammatory and non-degenerative neurological

conditions, but these metabolites were significantly

increased in a sample of post-mortem caudate speci-

mens (Yao et al., 2004). The disparate sample sizes,

patient characteristics, tissue specimen types and

substances measured in these studies, and the many

inherent metabolic variables in any given individual,

make direct comparison of these results difficult,

although they support the presence of abnormal NO

metabolism in schizophrenia.

Similarly, studies involving blood assays of intrinsic

antioxidants have collectively demonstrated signifi-

cantly altered antioxidant activities. Deficiency of

glutathione, the major intracellular antioxidant, in

its reduced form (GSH), has been observed and

suggested to be of pathophysiological significance

in schizophrenia as early as 1934 (Looney and Childs,

1934), although differences did not reach statistical

significance in that study. Significant GSH deficiency

has subsequently been reported (Altuntas et al., 2000).

Reduced levels of the major antioxidant enzymes,

superoxide dismutase (SOD), catalase (CAT) and glu-

tathione peroxidase (GSH-Px), have also been found in

patients with schizophrenia compared with controls

(Ben Othmen et al., 2007; Li et al., 2006; Ranjekar et al.,

2003). Others have reported unchanged levels for

these three enzymes (Srivastava et al., 2001), or altered

concentrations of individual enzymes (Abdalla et al.,

1986; Akyol et al., 2002; Altuntas et al., 2000; Dietrich-

Muszalska et al., 2005; Herken et al., 2001; Kuloglu

et al., 2002c; Zhang et al., 2006a). A strong negative

correlation between blood GSH-Px and structural

measures of brain atrophy was also reported by an

early study (Buckman et al., 1987). Furthermore, some

studies have differentiated enzymatic changes among

the schizophrenia subtypes (Herken et al., 2001;

Zhang et al., 2006a), and one study showed a linear

correlation between antioxidant enzyme levels and

positive symptom severity (Li et al., 2006). The anti-

oxidants uric acid (Yao et al., 1998b), albumin and

bilirubin (Yao et al., 2000), and the plasma total anti-

oxidant status (TAS) (Yao et al., 1998a) have also been

reported to be lower in patients with schizophrenia

than in controls. Albumin, bilirubin and uric acid were

shown to be significantly lower in neuroleptic-naive

patients with first-episode schizophrenia, results that

were independent of smoking status (Reddy et al.,

2003), thus strengthening the evidence for defective

antioxidant defence as an early pathophysiological

change associated with the disease, rather than a

sequela of drug effects, chronic disease and smoking.

Interestingly, the same study found no impairment of

antioxidative defence as determined using the same

indices, in those with first-episode affective psychosis

(Reddy et al., 2003), suggesting that oxidative stress

may be involved at different stages in the two groups

of disorders.

In tandem with the peripheral antioxidant ab-

normalities found in patients with schizophrenia,

post-mortem brain tissue studies have reported sig-

nificantly lower levels of glutathione in both its re-

duced (GSH) and oxidized forms (GSSG), and the two

enzymes responsible for conversions between these

two forms (GSH-Px, and glutathione reductase or GR),

in the caudate region from donors with schizophrenia

compared with those with other psychiatric conditions

and without psychiatric conditions. A concomitant

reduction in GSH:GSSG ratio, inverse correlations

between age and GSSG and between age and GR, as

well as the loss of normal correlations that exist in

Oxidative stress in psychiatric disorders 853

Table 1. Data relating to oxidative stress disturbances in schizophrenia

Comparedwith controls Sample size (n) of patients

Markers of oxidative disturbancesAssays of oxidants and antioxidantsNO metabolites Plasma Increased 100 (Akyol et al., 2002) ; 82 (Zoroglu et al., 2002) ; 46 (Yanik et al., 2003) ; 20

(Taneli et al., 2004) ; 46 (Li et al., 2006)Unchanged 62 (Srivastava et al., 2001)

PMN Decreased 62 (Srivastava et al., 2001)Platelet Unchanged 62 (Srivastava et al., 2001)CSF Decreased 10 (Ramirez et al., 2004)PM brain Increased 18 (Yao et al., 2004)

Glutathione Erythrocyte Decreased 48 (Altuntas et al., 2000)CSF Decreased 26 (Do et al., 2000)MRS Decreased 14 (Do et al., 2000)PM brain Decreased 12 (Yao et al., 2006a)

Antioxidativeenzymes

SOD Plasma Decreased 100 (Akyol et al., 2002) ; 92 (Zhang et al., 2006a)Erythrocyte Increased 50 (Abdalla et al., 1986) ; 48 (Altuntas et al., 2000) ; 25 (Kuloglu et al., 2002c)

Unchanged 65 (Herken et al., 2001)Decreased 31 (Ranjekar et al., 2003) ; 46 (Li et al., 2006) ; 60 (Ben Othmen et al., 2007)

PMN Unchanged 62 (Srivastava et al., 2001)Platelet Decreased 36 (Dietrich-Muszalska et al., 2005)PM brain Increased 13 (Michel et al., 2004)

CAT Erythrocyte Increased 65 (Herken et al., 2001)Decreased 31 (Ranjekar et al., 2003) ; 46 (Li et al., 2006) ; 60 (Ben Othmen et al., 2007)

PMN Unchanged 62 (Srivastava et al., 2001)GSH-Px Erythrocyte Increased 39 (Herken et al., 2001) ; 25 (Kuloglu et al., 2002c)

Unchanged 50 (Abdalla et al., 1986)Decreased 48 (Altuntas et al., 2000) ; 31 (Ranjekar et al., 2003) ; 46 (Li et al., 2006) ; 60

(Ben Othmen et al., 2007)PMN Unchanged 62 (Srivastava et al., 2001)Plasma Unchanged 100 (Akyol et al., 2002)

Decreased 92 (Zhang et al., 2006a)PM brain Decreased 12 (Yao et al., 2006a)

Uric acid Plasma Decreased 82 (Yao et al., 1998b)Albumin, bilirubin Plasma Decreased 81 (Yao et al., 2000)Total antioxidant status Plasma Decreased 45 (Yao et al., 1998a)

Assays of oxidative productsTBARS/MDA Plasma Increased 26 (Mahadik et al., 1998) ; 100 (Akyol et al., 2002) ; 25 (Kuloglu et al., 2002c) ; 92 (Zhang

et al., 2006a) ; 47 (Dietrich-Muszalska and Olas, 2007) ; 60 (Ben Othmen et al., 2007)Unchanged 31 (Ranjekar et al., 2003)

Erythrocyte Increased 48 (Altuntas et al., 2000) ; 65 (Herken et al., 2001)PMN Unchanged 62 (Srivastava et al., 2001)Platelet Increased 36 (Dietrich-Muszalska et al., 2005)CSF Decreased 10 (Skinner et al., 2005)

854F.Ngetal.

Isoprostanes Urine Increased 47 (Dietrich-Muszalska and Olas, 2007)DNA damage PM brain Increased 10 (Nishioka and Arnold, 2004)

Lymphocyte Unchanged 20 (Psimadas et al., 2004) ; 16 (Young et al., 2007)

Molecular and genetic studiesMolecular studies Altered proteins, RNA and metabolites relating to

mitochondrial function and oxidative stress pathways10, 54 (Prabakaran et al., 2004)

Susceptibility genes Glutamate cysteine ligase modifier (GCLM) subunit Multiple studies (Tosic et al., 2006)Glutamate cysteine ligase catalytic (GCLC) subunit 388 (Gysin et al., 2007)Manganese-SOD (-9Ala allele) 153 (Akyol et al., 2005)Glutathione S-transferase T1 (GSTT1) 292 (Saadat et al., 2007)ND4 subunit of NADH-ubiquinone reductase 181 (Marchbanks et al., 2003)

Antioxidant properties of antipsychoticsClinical studies Improvement of antioxidants¡MDA

disturbances with treatment41 (Zhang et al., 2003) ; 16 (Evans et al., 2003) ; 48 (Dakhale et al., 2004)

No reversal of oxidants, antioxidants¡MDA with treatment 20 (Taneli et al., 2004) ; 40 (Sarandol et al., 2007a)Preclinical studies Rats Reversal of haloperidol-

induced oxidative stressClozapine, olanzapine, risperidone (Pillai et al., 2007)

In-vitro cell studies Reversal of inducedoxidative stress

Olanzapine (Wei et al., 2003) ; clozapine, olanzapine, quetiapine,risperidone (Wang et al., 2005)

Antioxidant therapiesTrial design Treatment outcomes Sample size (n)

Vitamins C & E RCT; 8 wk; vitamin C vs. placebo adjunctive toantipsychotic treatment

Reversal of MDA and ascorbic acid levels ; superior BPRSoutcomes

40 (Dakhale et al., 2005)

Open-labelled; 4 months; adjunctive omega-3-fattyacids and vitamins C/E supplements

Symptomatic improvement ; no significant change in TBARS 33 (Arvindakshan et al., 2003a)

Improved positive and negative symptoms, extrapyramidalside-effects, SOD levels compared with baseline

17 (Sivrioglu et al., 2007)

Open-labelled; 2 wk; ascorbic acid adjunctiveto haloperidol

No symptomatic improvement 8 (Straw et al., 1989)

Ginkgo biloba extract RCT; 12 wk; EGb vs. placebo adjunctive to haloperidol Higher response rate; lower SAPS and SANS scores ;reversal of SOD levels

109 (Zhang et al., 2001a,b)

Single-blinded randomized trial ; 8 wk; EGb plusolanzapine vs. olanzapine alone

Lower SAPS scores ; reversal of SOD and CAT levels 29 (Atmaca et al., 2005)

NAC RCT; 6 months ; NAC vs. placebo adjunctive toantipsychotic treatment

Superior outcomes on CGI, PANSS, BAS 140 (Berk et al., unpublishedobservations)

BAS, Barnes Akathisia Scale ; BPRS, Brief Psychiatric Rating Scale ; CAT, catalase ; CGI, Clinical Global Impressions ; CSF, cerebrospinal fluid; EGb, Ginkgo biloba extract ; GSH-Px,glutathione peroxidase ; MDA, malondialdehyde; MRS, magnetic resonance spectroscopy; NAC, N-acetylcysteine ; NO, nitric oxide; PANSS, Positive and Negative Symptoms Scale ;PM, post-mortem; PMN, polymorphonucleocyte ; RCT, randomized controlled trial ; RNA, ribonucleic acid; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for theAssessment of Positive Symptoms; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances.

Oxidative

stressin

psychiatricdisorders

855

dynamic equilibrium, were also identified in the

schizophrenia group (Yao et al., 2006a). Together,

these findings indicate the presence of disturbed

redox coupling mechanisms in schizophrenia, which

may be related to GSH deficiency and/or time-related

reductions in GSSG and GR activities (Yao et al.,

2006a). Another post-mortem study examined a num-

ber of cortical and subcortical areas from donors

with schizophrenia and controls, and found elevated

levels of two SOD isoenzymes in the frontal cortex and

substantia innominata of those with schizophrenia,

thereby suggesting neuroanatomical specificity of

redox disturbances in schizophrenia (Michel et al.,

2004). Further supportive evidence is provided by a

study reporting a 27% reduction in the CSF glutathione

level in neuroleptic-naive patients with schizophrenia

compared with controls, which coexisted with a 52%

glutathione reduction in the medial prefrontal cortex,

as measured by magnetic resonance spectroscopy (Do

et al., 2000). The low CSF glutathione appears to be

consistent with previous findings of decreased levels

of its metabolite, c-glutamylglutamine, in the CSF of

schizophrenia patients (Do et al., 1995).

Assays of oxidative products

Estimating levels of oxidative reactive products pro-

vide another useful strategy to determine the impact

of oxidative stress. Published studies have predomi-

nantly examined products of lipid peroxidation

and DNA oxidation as markers of oxidative damage.

A widely used method of measuring lipid peroxi-

dation is the performance of thiobarbituric acid

reactive substances (TBARS) assays. TBARS are low-

molecular-weight substances, consisting largely of

malondialdehyde (MDA), which are formed from the

decomposition of unstable lipid peroxidation products

and react with thiobarbituric acid to form fluorescent

adducts (Fukunaga et al., 1998). TBARS have been

reported to be elevated in the plasma (Akyol et al.,

2002; Dietrich-Muszalska and Olas, 2007; Kuloglu

et al., 2002c; Mahadik et al., 1998; Ranjekar et al., 2003;

Zhang et al., 2006a), erythrocytes (Altuntas et al., 2000;

Herken et al., 2001), leucocytes (Srivastava et al.,

2001) and platelets (Dietrich-Muszalska et al., 2005)

of schizophrenia patients, in conjunction with abnor-

malities in antioxidant levels, and depleted essential

polyunsaturated fatty acids,which are especially prone

to lipid peroxidation (Arvindakshan et al., 2003b;

Khan et al., 2002). Data on CSF levels of TBARS in

schizophrenia are limited, but one small study has

been published, reporting reduced levels in a group

of actively psychotic patients compared with controls

(Skinner et al., 2005). This unexpected finding raises

questions about the origins of the elevated blood

TBARS that has been broadly reported in the litera-

ture, although the CSF results may have been

confounded by diminished neuronal membrane sub-

strates in the patient cohort (Skinner et al., 2005) and

replication of the study is required. The F2 iso-

prostanes, products of the free radical-induced oxi-

dation of arachidonic acid, have been suggested to

be superior to TBARS as markers of lipid peroxidation,

and a marked increase of urinary 8-isoprostaglandin

F2a has recently been reported in a sample of schizo-

phrenia patients compared with healthy controls

(Dietrich-Muszalska and Olas, 2007).

A smaller collection of studies has been published

in relation to markers of DNA damage in schizo-

phrenia. A post-mortem study examining the hippo-

campi of patients with ‘poor outcome’ schizophrenia

and non-psychiatric controls, found a ten-fold higher

presence of neuronal 8-hydroxy-2’-deoxyguanosine

(8-OhdG) among the patients compared with controls,

which correlatedwith elevated quantities of a cell-cycle

activation marker (Ki-67) (Nishioka and Arnold, 2004).

One study reported a trend increase in lymphocyte

DNA damage in schizophrenia patients compared

with control subjects (Young et al., 2007), but another

found no difference, although those with schizo-

phrenia showed a non-significant increase in sensi-

tivity to externally inducedDNAdamage and decrease

in DNA repair efficiency (Psimadas et al., 2004).

Molecular and genetic studies

Evidence from molecular and genetic studies support

fundamental redox disturbances in the aetiopatho-

genesis of schizophrenia. In an integrative study of

post-mortem prefrontal cortex, using a parallel trans-

criptomics, proteomics and metabolomics approach,

a large proportion of alterations on the transcript,

protein and metabolite levels were demonstrated to be

associated with mitochondrial function, energy meta-

bolism and oxidative stress responses. Furthermore,

almost 90% of schizophrenia patients could be dif-

ferentiated from controls in this study, including

neuroleptic-naive patients and those with <1 yr of

overt illness, based on a set of genes that encode for

mitochondrial complexes and redox-sensing proteins

(Prabakaran et al., 2004). This provides persuasive

evidence that mitochondrial function and oxidative

stress pathways are intrinsically involved in the patho-

genesis of the disorder, although the exact nature of

their roles, in particular whether they are primary or

secondary changes, are yet to be clarified.

856 F. Ng et al.

Other studies have identified links between schizo-

phrenia and specific genes, such as those for the key

glutathione-synthesizing enzyme, glutamate cysteine

ligase modifier (GCLM) subunit (Tosic et al., 2006),

and for the antioxidant enzymes manganese super-

oxide dismutase (Mn-SOD) (Akyol et al., 2005) and

glutathione S-transferase T1 (GSTT1) (Saadat et al.,

2007). The glutamate cysteine ligase (GCL) connection

seems particularly promising, in view of recent data

indicating reduced GCL activity, decreased expression

of its catalytic subunit (GCLC), and GCLC poly-

morphism in those with schizophrenia (Gysin et al.,

2007). A mitochondrial DNA sequence variation

affecting a subunit of NADH-ubiquinone reductase

(Complex I), a component of the electron transport

chain responsible for generating superoxide, has also

been associated with schizophrenia patients and with

increased superoxide levels in post-mortem brain

samples (Marchbanks et al., 2003). On a related sub-

ject, polymorphism of the glutathione S-transferase

pi gene (GSTP1) has been reported to be associated

with vulnerability to develop psychosis in the setting

of methamphetamine abuse (Hashimoto et al., 2005),

which may have some bearing on schizophrenia.

Antioxidant properties of antipsychotics

Clinical studies

Antioxidant effects of established antipsychotic agents

provide indirect evidence for oxidative pathophysio-

logical mechanisms in schizophrenia. Abnormalities in

levels of antioxidants and oxidative products have

been reported to reverse over the course of treatment

with atypical antipsychotics, coinciding with sympto-

matic improvement (Dakhale et al., 2004; Zhang et al.,

2003). In two published studies, baseline serum SOD

(Dakhale et al., 2004; Zhang et al., 2003), MDA and

ascorbic acid (Dakhale et al., 2004) levels in patients

with schizophrenia significantly differed from those in

age- and sex-matched controls, taking smoking status

into consideration. Within the patient groups, their

baseline levels significantly shifted towards normality

after treatment with atypical antipsychotics over the

study durations of 8 wk (Dakhale et al., 2004) and

12 wk (Zhang et al., 2003), respectively. Another study

with a smaller sample size conducted over 6 months

likewise showed normalization of the antioxidative

enzymes SOD, CAT and GSH-Px with treatment

(Evans et al., 2003). These oxidative marker changes

correlated with symptomatic improvements as

measured by validated scales, further substantiating

an intrinsic link between oxidative stress status and

psychotic symptomatology. In contrast, others did not

find significant changes in a number of oxidative-

antioxidative parameters (Sarandol et al., 2007a) or in

serum NO metabolites (Taneli et al., 2004). Membrane

essential polyunsaturated fatty acids (EPUFAs)

depletion has been reported in schizophrenia, with

one proposed mechanism being oxidative peroxi-

dation (Evans et al., 2003; Khan et al., 2002; Ranjekar

et al., 2003). Data showing repletion of EPUFAs with

treatment (Evans et al., 2003) and higher levels of

EPUFAs in medicated patients with chronic schizo-

phrenia compared with never-medicated first-episode

patients (Khan et al., 2002), although inconclusive,

suggest an ameliorating effect of antipsychotics on

disease-related oxidative stress status.

A differential impact on oxidative stress status may

exist between typical and atypical antipsychotic medi-

cations. Higher levels of lipid peroxidation products

have been reported in patients treated with typical

than atypical drugs (Kropp et al., 2005), but contra-

dictory results were reported by others (Gama et al.,

2006; Zhang et al., 2006a). The differing pro-oxidant

potentials of the antipsychotics have been postulated

as a mediating factor in the more common develop-

ment of tardive dyskinesia with typical agents

(Andreassen and Jorgensen, 2000).

Preclinical studies

Animal data have demonstrated elevated oxidative

stress markers with 45-d and 90-d administration of

haloperidol, but not atypicals (Parikh et al., 2003). In

extending this study in rats to 180 d, haloperidol was

again associated with the greatest level of oxidative

stress, but oxidative stress as gauged by significant

reductions in enzymatic activities were also seen with

chlorpromazine and the atypical agents ziprasidone,

risperidone and olanzapine. Both typical and atypical

agents were associated with increased lipid peroxi-

dation after 180 d, except for olanzapine. In addition,

clozapine, olanzapine, and to a lesser extent risper-

idone, were able to reverse the changes induced by

haloperidol (Pillai et al., 2007). Haloperidol-induced

oxidative stress parameters in rats have also been

shown to be ameliorated by the antioxidant drug, N-

acetylcysteine (NAC) (Harvey et al., 2007). In-vitro

cell studies have demonstrated a protective effect of

atypicals, such as olanzapine and quetiapine, on PC12

cells exposed to oxidative stress (Wang et al., 2005;

Wei et al., 2003).

Antioxidant therapies

Clinical trials investigating adjunctive antioxidants

in the treatment of schizophrenia have utilized


vitamins C and E, Ginkgo biloba extract (EGb), and

NAC.

Vitamins C and E

The vast majority of vitamin E studies in schizo-

phrenia has focused on its preventive and therapeutic

roles in tardive dyskinesia. Conflicting results have

been found for dyskinetic symptoms (Adler et al., 1998,

1999), but some have reported efficacy in psycho-

pathology (Lohr and Caligiuri, 1996). A small (n=40)

randomized, controlled trial comparing vitamin C and

atypical antipsychotics with atypical antipsychotics

alone (placebo) found that at the end of 8 wk, the

baseline plasma ascorbic acid and MDA abnormalities

had been significantly reversed in the vitamin C group

compared with the placebo group. Symptomatic out-

come, as measured with the Brief Psychiatric Rating

Scale (BPRS), was also significantly better for the

vitamin C group (Dakhale et al., 2005). Other studies

reported positive treatment outcomes, in terms of

symptoms, functioning and extrapyramidal side-

effects, with the supplementation of a combination

of omega-3-fatty acids and vitamins C and E

(Arvindakshan et al., 2003a; Sivrioglu et al., 2007).

However, these findings are difficult to interpret

in view of the small sample sizes (n=17 and n=33),

the studies’ open-label and non-randomized designs,

and concomitant use of antioxidants and poly-

unsaturated fatty acids. Lack of efficacy was reported

by a small (n=8), 2-wk open-label trial of vitamin C

(Straw et al., 1989).

Ginkgo biloba extract

A small body of literature has suggested efficacy

of supplementary EGb in schizophrenia. In a 12-wk,

double-blind, randomized trial comparing EGb and

placebo adjunctive to haloperidol in treatment-

resistant patients with schizophrenia (n=109), those

treated with EGb showed superior outcomes as

measured by a higher response rate (57.1% vs. 37.7%)

and significant score reductions on the Scale for the

Assessment of Positive Symptoms (SAPS) and Scale

for the Assessment of Negative Symptoms (SANS).

Scores on these scales did not significantly vary in the

placebo group, although both groups improved on

BPRS scores. Furthermore, treatment-emergent behav-

ioural and neurological side-effects were significantly

lower in the EGb group (Zhang et al., 2001b). This

group also showed superior improvements in peri-

pheral T cell subsets (CD3+, CD4+, CD8+ and IL-2-

secreting cells), which were diminished at baseline

(Zhang et al., 2006b). These authors additionally

reported elevated pre-treatment SOD levels among

patients with treatment-resistant schizophrenia,

correlating with positive symptomatic severity, which

was selectively reduced in patients receiving EGb but

not placebo (Zhang et al., 2001a, 2006b; Zhou et al.,

1999), thereby suggesting that antioxidant activity,

schizophrenia symptoms and peripheral immune

functions may be interrelated. A confounder in this

group of studies is the use of haloperidol as treatment

base, which through its potential in inducing oxidative

stress and cognitive blunting, may have added iatro-

genic complexities to the disease and treatment pro-

cess, such that it is difficult to determine whether

the superior outcomes were due to lessened adverse

effects, underlying psychopathology, or both. This

concern was minimized in a subsequent placebo-

controlled trial of EGb adjunctive to olanzapine,

which also found significantly lower SAPS scores,

SOD and CAT levels among the EGb group, although

this study had other limitations, such as its single-

blinded design and underpowered sample size

(n=29) (Atmaca et al., 2005).

N-acetylcysteine

NAC is a cysteine prodrug with high bioavailability,

which is thought to exert antioxidative effects primar-

ily through enhancing stores of the major intracellular

antioxidant, glutathione, by stimulating its formation

from cysteine (Atkuri et al., 2007). A series of experi-

ments using an animal model has demonstrated that

the pharmacodynamic actions of NAC involve the

cystine-glutamate antiporter and extrasynaptic group

II metabotropic glutamate receptors (mGluR) (Baker

et al., 2007). This may have particular relevance in

schizophrenia, as glutamatergic dysfunction has been

implicated as a pathophysiological pathway (Goff and

Coyle, 2001).

NAC has been studied as an adjunctive treatment

in schizophrenia in a recently completed 6-month,

double-blind, randomized, placebo-controlled trial

(n=140), which found significant advantages of NAC

over placebo on several scales that include the Clinical

Global Impressions (CGI) (effect size of 0.43), the

Positive and Negative Symptoms Scale (PANSS) (ef-

fect size of 0.57) and the Barnes Akathisia Scale (BAS)

(effect size of 0.44) (Berk et al., unpublished obser-

vations). In a subset of patients enrolled in this study

(n=11), NAC was also associated with an increase in

plasma glutathione and the amelioration of mismatch

negativity, an auditory evoked potential component

characteristically impaired in schizophrenia, which

may indicate the ability of NAC to correct more

858 F. Ng et al.

fundamental neurophysiological dysfunction (Lavoie

et al., 2007).

Bipolar disorder

Similar types of studies, albeit more limited in scope,

have provided evidence for oxidative dysfunction in

bipolar disorder (Table 2). The majority is derived

from biochemical and pharmacological data.


Oxidative disturbances have been demonstrated in

both animal models and human studies.

Animal studies

In animal models of mania, where amphetamine was

administered to rats, raised levels of protein oxidation

markers were detected in brain tissues following both

single and repeated dosing, with the additional in-

duction of lipid peroxidation markers on repeated ex-

posure (Frey et al., 2006a). Exposure to amphetamine

has also been linked to SOD and CAT alterations (Frey

et al., 2006c), as well as to increased superoxide pro-

duction in submitochondrial particles in the rat brain

(Frey et al., 2006b). In these studies, the striatum,

hippocampus and prefrontal cortex have shown dif-

ferential vulnerability and adaptivity (Frey et al.,

2006a, c).

Human assays of oxidants, antioxidants and oxidative

products

Human data of oxidative markers in bipolar disorder

are often derived from studies with patient samples

that include other psychiatric disorders. In two such

studies, increased SOD activities as compared with

healthy controls were associated with both bipolar

disorder and schizophrenia (Abdalla et al., 1986;

Kuloglu et al., 2002c), whereas another study found

a trend for reduced SOD in bipolar disorder and sig-

nificantly reduced CAT levels for both groups

(Ranjekar et al., 2003). However, GSH-Px changes

were reported for schizophrenia only (Kuloglu et al.,

2002c; Ranjekar et al., 2003). An increase in the lipid

peroxidation product, TBARS, was also reported for

both bipolar disorder and schizophrenia (Kuloglu

et al., 2002c), as was a decrease in EPUFAs (Ranjekar

et al., 2003). In a study involving patients with bipolar

disorder, major depressive disorder and schizoaffec-

tive disorder, the pooled data showed reduced NO,

CAT and GSH-Px levels, unchanged SOD and elevated

MDA levels compared with controls, but the results

were not analysed according to diagnosis (Ozcan et al.,

2004).

A comparatively large study was conducted solely

on bipolar disorder patients, who were at various

phases of the illness, thus allowing the exploration of

phase-specific changes in oxidative stress status.

Interestingly, raised TBARS levels were observed re-

gardless of illness phase, whereas GSH-Px activity was

only elevated in euthymia but not in depressed or

manic phases. Increased SOD activity was associated

with manic and depressive episodes but not euthymia,

and CAT reduction with mania and euthymia but

not depression (Andreazza et al., 2007). An oxidative

profile consistent with these findings were reported in

a twin case report of mania (Frey et al., 2007).

However, another study reported lowered SOD levels

in bipolar depression, in conjunction with elevated

NO levels (Selek et al., 2007). In a study comparing

both unmedicated and lithium-treated patients in

manic episodes with healthy controls, TBARS, SOD

and CAT levels were significantly higher in manic

patients compared with controls, with the lithium-

treated group showing lower levels of TBARS and

SOD than unmedicated patients, suggesting possible

corrective effects of lithium on oxidative parameters

(Machado-Vieira et al., 2007). Elevated NO and nitrite

levels have been reported in bipolar disorder patients

(Gergerlioglu et al., 2007; Savas et al., 2006; Yanik et al.,

2004b), and have been correlated with the number of

manic episodes (Gergerlioglu et al., 2007; Savas et al.,

2006).


Genetic studies have identified certain polymorphisms

in bipolar disorder patients that play a role in oxidat-

ive homeostasis. A single-nucleotide polymorphism

of the TRPM2 gene, which encodes for a calcium

channel receptor, has been strongly associated with

bipolar disorder and is understood to cause cellular

calcium dysregulation in response to oxidative stress

(McQuillin et al., 2006). Dysregulation of second-

messenger calcium has been described in bipolar dis-

order, and the modulation of this is thought to be a

therapeutic mediating mechanism of lithium (Berk

et al., 1995, 1996). Innate dysregulation of the

apoptosis and oxidative processes has been suggested

by a recent study, in which the hippocampal ex-

pression of genes encoding DNA repair and anti-

oxidant enzymes were found to be down-regulated in

bipolar disorder, while many apoptosis genes were

up-regulated (Benes et al., 2006).

A related theoretical framework for the patho-

physiology of bipolar disorder has centred on impaired

mitochondrial metabolism as the primary defect in


Table 2. Data relating to oxidative stress disturbances in bipolar disorder

Compared

with controls Sample size (n) of patients


Assays of oxidants and antioxidants

NO metabolites Serum Increased 43 (Yanik et al., 2004b); 27 (euthymia) (Savas et al.,

2006); 30 (depressed phase) (Selek et al., 2007) ;

29 (manic phase) (Gergerlioglu et al., 2007)

Erythrocyte Decreased 30 (18 bipolar disorder; 12 other affective

disorders) (Ozcan et al., 2004)

Antioxidative

enzymes

SOD Plasma or serum Increased 27 (euthymia) (Savas et al., 2006); 84 (manic and

depressed phases only) (Andreazza et al., 2007);

45 (manic phase) (Machado-Vieira et al., 2007)

Decreased 30 (depressed phase) (Selek et al., 2007); 29

(manic phase) (Gergerlioglu et al., 2007)

Erythrocyte Increased 20 (Abdalla et al., 1986); 23 (Kuloglu et al., 2002c)

Unchanged 10 (Ranjekar et al., 2003); 30 (18 bipolar disorder;

12 other affective disorders) (Ozcan et al., 2004)

CAT Plasma or serum Increased 45 (manic phase) (Machado-Vieira et al., 2007)

Decreased 84 (manic phase and euthymia only) (Andreazza

et al., 2007)

Erythrocyte Decreased 10 (Ranjekar et al., 2003); 30 (18 bipolar disorder;

12 other affective disorders) (Ozcan et al., 2004)

GSH-Px Serum Increased 84 (euthymia only) (Andreazza et al., 2007)

Erythrocyte Unchanged 20 (Abdalla et al., 1986); 23 (Kuloglu et al., 2002c);

10 (Ranjekar et al., 2003)

Decreased 30 (18 bipolar disorder; 12 other affective


Assays of oxidative products

TBARS/MDA Plasma or serum Increased 23 (Kuloglu et al., 2002c); 84 (Andreazza et al.,

2007); 45 (manic phase) (Machado-Vieira et al.,

2007)

Unchanged 10 (Ranjekar et al., 2003)

Erythrocyte Increased 30 (18 bipolar disorder; 12 other affective



Susceptibility genes TRPM2 600 (McQuillin et al., 2006)

Increased expression of neuronal NOS1, altered

expression of GSH-Px 4, glyoxylase, esterase

D-formylglutathione hydrolase, glutathione

synthetase, glutathione S-transferase A2,

M5 and omega, CAT, SOD

9 (Benes et al., 2006)

Antioxidant properties of established therapeutic agents

Clinical studies Improvement of lowered SOD but no significant

change in NO elevation with treatment in manic

patients

29 (Gergerlioglu et al., 2007)

Improvement of reduced GSH-Px with treatment 30 (18 bipolar disorder; 12 other affective


Improvement of elevated SOD and TBARS in

the twin treated for mania compared with the

other twin who refused anti-manic treatment

Monozygotic twin case study (Frey et al., 2007)

Rise in blood GSH 2–4 h after ECT 20 (mixed diagnoses) (Henneman and

Altschule, 1951)

860 F. Ng et al.

bipolar disorder (Kato, 2006; Young, 2007). This con-

cept is supported by data from a number of sources,

including magnetic resonance spectroscopy evidence

of decreased brain energy metabolism, maternal

hereditary patterns, comorbid mitochondrial diseases,

mitochondrial mechanisms of mood stabilisers, and

mitochondrial DNA deletions, mutations and poly-

morphisms (Kato, 2007).

Antioxidant properties of established therapeutic

agents

Clinical studies

Indirect support for the pathophysiological role of

oxidative stress in bipolar disorder comes from clinical

studies that demonstrate normalisation of oxidative

parameters over the course of treatment (Frey et al.,

2007; Gergerlioglu et al., 2007; Henneman and

Altschule, 1951; Ozcan et al., 2004). This has been el-

egantly illustrated by a case report of twins presenting

with mania, where increased TBARS, SOD and DNA

damage, and decreased CAT were observed in both

patients prior to treatment. Whilst the twin who was

successfully treated showed normalization of TBARS

and SOD, the oxidative parameters remained un-

changed for the other twin who refused treatment and

continued to be manic (Frey et al., 2007). In addition,

the evidence behind the antioxidant properties of

antipsychotics is also relevant for bipolar disorder,

considering their efficacy in its treatment, particularly

of mania. An early study of psychiatric patients, in-

cluding those with bipolar disorder, also bears some

relevance to the current discussion through demon-

strating a rise in blood glutathione 2–4 h following

electroconvulsive therapy (Henneman and Altschule,

1951).

Preclinical studies

The antioxidant properties of mood stabilisers have

been further strengthened by findings from animal

Table 2 (cont.)

Agent studied

Preclinical

studies

Rats Prevention/reversal of lipid

peroxidation in rat model of mania

Lithium, valproate (Frey et al., 2006d)

Lithium increased total antioxidant

reactivity, increased SOD, and reduced

ROS formation; unable to prevent

stress-induced disturbances in

oxidative parameters

Lithium (de Vasconcellos et al., 2006)

In-vitro

cell

studies

Inhibited ferric chloride-induced lipid

peroxidation and protein oxidation

Valproate (Wang et al., 2003)

Inhibited glutamate-induced MDA,

protein carbonyls, DNA fragmentation

and cell death

Lithium, valproate (Shao et al., 2005)

Inhibited hydrogen peroxide-induced

cell death; increased GSH and

GCL expression

Lithium, valproate, carbamazepine,

lamotrigine (Cui et al., 2007)

Cytoprotective effects against hydrogen

peroxide-induced neural cell death

Lithium, valproate (Lai et al., 2006)


Trial design Treatment outcomes Sample size (n)

NAC RCT; 6 months; NAC vs. placebo

adjunctive to treatment-as-usual

Superior outcomes on BDRS, MADRS

and functional measures

75 (Berk, 2007)

BDRS, Bipolar Depression Rating Scale; CAT, catalase; ECT, electroconvulsive therapy; GCL, glutamate cysteine ligase;

GSH, reduced glutathione; GSH-Px, glutathione peroxidase; MADRS, Montgomery–Asberg Depression Rating Scale; MDA,

malondialdehyde; NAC, N-acetylcysteine; NOS1, nitric oxide synthase; ROS, reactive oxygen species; SOD, superoxide

dismutase; TBARS, thiobarbituric acid reactive substances.


and cell studies. In a rat model of mania using am-

phetamine, both lithium and valproate were able to

prevent and reverse amphetamine-induced hyper-

activity, prevent lipid peroxidation in the hippocam-

pus and reverse lipid peroxidation in the prefrontal

cortex. No alterations were seen for protein carbonyl

formation in this model, and changes in antioxidant

enzymes were variable (Frey et al., 2006d). Others

have supported the antioxidant effects of lithium, but

have not found it able to prevent stress-induced oxi-

dative damage in rats (de Vasconcellos et al., 2006).

Treatment with valproate has been shown to inhibit

lipid peroxidation and protein oxidation in primary

cultured rat cerebrocortical cells exposed to an oxidant

(Wang et al., 2003). Using similar cell cultures, treat-

ment with lithium or valproate was also shown to in-

hibit the glutamate-induced intracellular calcium

release, lipid peroxidation, protein oxidation, DNA

fragmentation and cell death (Shao et al., 2005). Other

cell culture studies have associated lithium and

valproate with increased expression of the endoplas-

mic reticulum stress proteins GRP78, GRP94 and cal-

reticulin (Chen et al., 2000; Shao et al., 2006), increased

levels of the anti-apoptotic factor bcl-2 (Chen et al.,

1999), glutathione and glutamate-cysteine ligase (Cui

et al., 2007), and reduced cytochrome c release and

caspase-2 activation (Lai et al., 2006), thereby implying

that multiple pharmacodynamic actions may underlie

the neuroprotective effects of these agents against

oxidative stress. However, increased glutathione levels

and glutamate-cysteine ligase gene expression found

with other mood stabilizers such as carbamazepine

and lamotrigine suggest that glutathione may be a

common neuroprotective target among mood stabi-

lizers (Cui et al., 2007). Furthermore, evidence from

human cell studies have found neuroprotective effects

from lithium and valproate in neural but not glial cells

(Lai et al., 2006), suggesting a specificity to their

therapeutic effects.


Clinical studies

A recent randomized, placebo-controlled trial of

adjunctive NAC in the treatment of bipolar disorder

(n=75) has shown favourable outcomes, as assessed

by a number of symptomatic, global and functional

scales. The primary findings were improvement in

depressive symptomatology, on both the Bipolar De-

pression Rating Scale (BDRS) and the Montgomery–

Asberg Depression Rating Scale (MADRS), with sig-

nificant benefits on functioning and quality of life

also documented (Berk, 2007).

Preclinical studies

In the rat model of mania, pre-treatment with

NAC significantly attenuated the methamphetamine-

induced hyperlocomotion, behavioural sensitization,

and striatal dopamine depletion in a dose-dependent

fashion (Fukami et al., 2004).

Depression

There is evidence for oxidative disturbances in major

depression, as demonstrated by oxidative marker

studies and those examining the antioxidant effects

of antidepressants (Table 3). There is no data of anti-

oxidants as therapeutic agents for this condition.


Animal studies

Data from animal models have demonstrated the de-

pletion of glutathione (Pal and Dandiya, 1994), re-

duction of GSH-Px and vitamin C, and rise in lipid

peroxidation and NO (Eren et al., 2007b) in association

with stress-induced behavioural depression.

Human assays of oxidants, antioxidants and

oxidative products

Human studies have reported a number of oxidative

disturbances in patients with major depression, in-

cluding oxidative damage in erythrocytic membranes

as suggested by the depletion of omega-3 fatty acids

(Peet et al., 1998); elevated lipid peroxidation products

(Bilici et al., 2001; Khanzode et al., 2003; Sarandol

et al., 2007b; Selley, 2004) ; oxidative DNA damage

(Forlenza andMiller, 2006) ; reduced serum vitamins C

(Khanzode et al., 2003) and E (Maes et al., 2000; Owen

et al., 2005), the latter of which was not accounted for

by dietary insufficiency (Owen et al., 2005) ; increased

concentrations of the endogenous inhibitor of endo-

thelial NO synthase asymmetric dimethylarginine

(ADMA) (Selley, 2004) and decreased NO (Selley,

2004; Srivastava et al., 2002). Albumin, which has

antioxidant activity, has also been reported to be

compromised in major depression (Van Hunsel et al.,

1996). Findings of altered antioxidant enzyme levels

have been mixed, with reports of elevated SOD (Bilici

et al., 2001; Khanzode et al., 2003; Sarandol et al.,

2007b), GSH-Px and GR (Bilici et al., 2001), diminished

SOD (Herken et al., 2007), and no change (Srivastava

et al., 2002). In one study of major depressive disorder

patients who had been medication-free for at least

2 months, the plasma total antioxidant potential and

862 F. Ng et al.

Table 3. Data relating to oxidative stress disturbances in major depressive disorder

Compared with controls Sample size (n) of patients

Markers of oxidative disturbancesAssays of oxidants and antioxidantsNOmetabolites

Plasma Decreased 25 (Selley, 2004)Serum Unchanged 36 (Herken et al., 2007)PMN Decreased 30 (Srivastava et al., 2001)

Peroxide Plasma Increased 21 (Yanik et al., 2004a)Antioxi-dativeenzymes

SOD Serum Increased 62 (Khanzode et al., 2003)Decreased 36 (Herken et al., 2007)

Erythrocyte Increased 12, 18 (Bilici et al., 2001) ; 96(Sarandol et al., 2007b)

PMN Unchanged 15 (Srivastava et al., 2001)CAT Erythrocyte Unchanged 12, 18 (Bilici et al., 2001)

PMN Unchanged 26 (Srivastava et al., 2001)GSH-Px Plasma Unchanged 12, 18 (Bilici et al., 2001)

Erythrocyte Increased 12 (Bilici et al., 2001)Unchanged 18 (Bilici et al., 2001)

PMN Unchanged 12 (Srivastava et al., 2001)Vitamin C Plasma Decreased 62 (Khanzode et al., 2003)Vitamin E Plasma or serum Decreased 42 (Maes et al., 2000) ; 49 (Owen et al., 2005)Albumin, totalserum protein

Plasma or serum Decreased 37 (Van Hunsel et al., 1996)

Uric acid Plasma Decreased 21 (Yanik et al., 2004a)Total anti-oxidantpotential

Plasma Decreased 21 (Yanik et al., 2004a)

Assays of oxidative productsTBARS/MDA Plasma or serum Increased 12, 18 (Bilici et al., 2001) ; 62 (Khanzode et al.,

2003) ; 96 (Sarandol et al., 2007b)Erythrocyte Increased 12, 18 (Bilici et al., 2001) ; 96 (Sarandol et al.,

2007b)HNE Plasma Increased 25 (Selley, 2004)8-OHdG Serum Increased 84 (Forlenza and Miller, 2006)

Antioxidant properties of antidepressantsClinicalstudies

Improved lipid peroxidation andantioxidative enzyme levels aftertreatment with SSRIs for 3months

30 (Bilici et al., 2001)

Improved MDA, SOD and vitamin Clevels with SSRIs for 3 months

62 (Khanzode et al., 2003)

Improved SOD and NO levels afterantidepressant treatment for 8 wk

36 (Herken et al., 2007)

No significant changes in oxidative markerswith 6 wk of antidepressant treatment

96 (Sarandol et al., 2007b)

Preclinicalstudies

Mice Replenish glutathione depletion;prevent and/or reverse shock-induced behavioural depression

Imipramine, maprotiline, fluvoxamine,trazodone (Pal and Dandiya, 1994)

Rats Correction of GSH-Px, glutathione,vitamin C, and lipid peroxidation levelsin the stress-induced depression model

Venlafaxine (Eren et al., 2007b)

Modulation of antioxidant proteins Venlafaxine, fluoxetine (Khawaja et al., 2004)Improvement of depression-relatedlipid peroxidation, and GSH-Px,glutathione and vitamin C depletion

Lamotrigine, aripiprazole, escitalopram(Eren et al., 2007a)

In-vitrocell studies

Attenuate anoxia- andglutamate-induced cell death

Moclobemide (Verleye et al., 2007)

Attenuate cell loss from chemicaloxidative stress ; antioxidant effects

Phenelzine (Lee et al., 2003)

8-OhdG, 8-hydroxy-2’-deoxyguanosine; CAT, catalase; GR, glutathione reductase; GSH-Px, glutathione peroxidase ; HNE,(E)-4-Hydroxy-2-nonenal; MDA, malondialdehyde; NO, nitric oxide; PMN, polymorphonucleocyte ; SOD, superoxidedismutase ; SSRI, selective serotonin reuptake inhibitor ; TBARS, thiobarbituric acid reactive substances.


uric acid were reduced in patients compared with

controls, whereas their total plasma peroxide levels

and oxidative stress index were both higher (Yanik

et al., 2004a). Moreover, a significant positive corre-

lation was found between oxidative stress index and

the Hamilton Depression Rating Scale (HAMD) (Yanik

et al., 2004a). Similarly, other studies have also re-

ported correlations between depressive severity and

the magnitude of disturbances in their respective

oxidative indices (Bilici et al., 2001; Forlenza and

Miller, 2006; Owen et al., 2005; Sarandol et al., 2007b),

although one study found no such relationship

(Herken et al., 2007).

The enhanced oxidation of apolipoprotein B-

containing lipoproteins, correlating with the severity

of major depression, along with significant reductions

in serumparaoxonase/arylesterase activities following

antidepressant treatment, have been demonstrated

(Sarandol et al., 2006). As oxidation of lipoproteins

and low paraoxonase activity have been implicated

in atherogenesis and coronary artery disease, these

results may be relevant in understanding the link be-

tween major depression and cardiovascular disease

(Sarandol et al., 2006). Others have also suggested

oxidative changes, such as cumulative oxidative DNA

damage, to be a common pathophysiological mech-

anism underlying major depression and medical co-

morbidities (Forlenza and Miller, 2006).

Antioxidant properties of antidepressants

Clinical studies

A small group of studies, by demonstrating reversals

of antioxidant and oxidative disturbances after anti-

depressant treatments, has provided evidence for

the antioxidant effects of these drugs (Bilici et al.,

2001; Herken et al., 2007; Khanzode et al., 2003).

Relating to this observation, oxidative parameters

have been nominated by some authors to be candidate

markers of antidepressant efficacy (Bilici et al., 2001;

Herken et al., 2007). However, studies have not

been unanimous in associating normalization of

oxidative parameters with antidepressant treatment.

One comparatively larger study found that 6 wk

of antidepressant treatment did not affect oxidative-

antioxidative systems, regardless of the response

or remission status of the patients (Sarandol et al.,

2007b).

For drugs other than antidepressants, the anti-

oxidant effects of lithium may also lend support

for oxidative stress mechanisms behind major de-

pression, as it has an established role as adjunctive

treatment.

Preclinical studies

In animal studies, antidepressants of different classes

have been shown to replenish, to varying degrees, the

glutathione depletion seen in the inescapable shock be-

havioural paradigm of depression (Pal and Dandiya,

1994). Venlafaxine was associated with the correction

of several depression-specific oxidative markers in the

rat cortex (Eren et al., 2007b). A proteomic study using

rats has found multiple protein modulations in the

hippocampus after venlafaxine or fluoxetine adminis-

tration. Antioxidant and anti-apoptotic proteins were

among those identified (Khawaja et al., 2004). In

another animal study, lamotrigine, aripiprazole and

escitalopram were all shown to improve depression-

related GSH-Px, glutathione and Vitamin C depletion,

and lipid peroxidation increase. Of the three drugs,

lamotrigine was associated with the greatest anti-

oxidative protective effects (Eren et al., 2007a). An in-

vitro study of rat cerebrocortex neuronal and astroglial

cultures showed that moclobemide could attenuate

cell death induced by anoxia and glutamate, a process

involving oxidative stress pathways (Verleye et al.,

2007). The monoamine oxidase inhibitor phenelzine

was able to attenuate the loss of differentiated rat

PC12 cells exposed to chemical oxidative stress, and

demonstrated antioxidant effects including the re-

duction of ROS formation and the scavenging of the

pro-oxidant hydrogen peroxide (Lee et al., 2003).


Preclinical studies

As no clinical trials of antioxidant therapies have been

published for major depressive disorder, the primary

evidence for antioxidant efficacy at present is derived

from the previously cited animal study, which demon-

strated the prevention and reversal of shock-induced

behavioural depression with glutathione (Pal and

Dandiya, 1994).

Indirect clinical studies

A small (n=16), open-label study of adjunctive EGb in

the treatment of patients with major depressive has

been published, reporting positive outcomes in terms

of improved sleep efficiency and awakenings, but de-

pressive outcomes were not reported (Hemmeter

et al., 2001). The beneficial effects of NAC on mood in

a non-clinically depressed population have been re-

ported from a double-blind, placebo-controlled study

of NAC in patients with mild chronic bronchitis. NAC

recipients showed significantly superior outcomes

on the General Health Questionnaire (GHQ), which

864 F. Ng et al.

predominantly measures mood, compared with the

placebo group (Hansen et al., 1994). The limitations to

generalizing these indirect results to depression are

apparent.

Anxiety disorders

The notion of oxidative stress mechanisms underlying

anxiety disorder has been in existence for some years,

with the earlier suggestion that NO and peroxynitrite

might play a major role in setting up a vicious aetio-

logical cycle involving free radicals and inflammatory

cytokines in post-traumatic stress disorder (Miller,

1999; Pall and Satterlee, 2001). However, oxidation

biology research in anxiety disorders is still at its in-

fancy, and the bulk of the limited literature originates

from animal studies, which have nevertheless gener-

ated intriguing findings.

Animal studies

An interesting set of animal experiments have linked

glyoxalase 1 (Glo1) and glutathione reductase 1 (GR)

genes, both of which protect against oxidative stress,

with anxiety in mice (Hovatta et al., 2005). By using

behavioural analysis of six inbred mouse strains to

determine anxiety phenotypes and quantitative gene

expression profiling of seven pertinent brain regions,

17 candidate genes were identified, of which both

Glo1 and GR showed positive correlations between

their expressed activity levels and phenotypic anxiety

status. The causal role that these genes may play in

anxiety were supported by a series of experiments,

which confirmed a highly significant positive corre-

lation between the expressed activities of these genes

and anxiety in cross-bred mice, and demonstrated

that over-expression of Glo1 and GR in the cingulate

cortex increased anxiety behaviours, while inhibition

of Glo1 gene expression reduced such behaviours

(Hovatta et al., 2005). The over-expression of Glo1 in

innately anxious mice has also been reported by others

(Landgraf et al., 2007).

Further evidence for oxidative pathways being in-

volved in mouse models of anxiety can be derived

from the association of vitamin E depletion and

increased oxidative stress markers and anxiety

behaviours in phospholipid transfer protein (PLTP)

knock-out mice (Desrumaux et al., 2005), and from a

positive correlation between peripheral blood oxidat-

ive stress markers and anxiety behaviours (Bouayed

et al., 2007b). The pro-oxidative vitamin A has been

demonstrated to induce oxidative stress in the rat

hippocampus, as measured by increased lipid per-

oxidation, protein carbonylation, protein thiol oxida-

tion, and altered SOD and CAT levels, as well as

causing anxiety behaviours in the animal model (de

Oliveira et al., 2007). In addition, green tea polyphenol

(–)-epigallocatechin gallate (EGCG), a potent anti-

oxidant, showed anxiolytic effects on mice with a

dose-dependent relationship (Vignes et al., 2006).

Anxiolytic effects have also been reported in mice

with chlorogenic acid, a dietary polyphenol and anti-

oxidant (Bouayed et al., 2007a). Inconsistent results

have been reported for whortleberry extracts in rats,

and vitamin E was found to increase anxiety in the

same study (Kolosova et al., 2006).

Human studies

In humans, only a handful of relevant studies have

been published. These have reported elevated lipid

peroxidation products and antioxidant changes in

obsessive–compulsive disorder (Ersan et al., 2006;

Kuloglu et al., 2002a), panic disorder (Kuloglu et al.,

2002b) and social phobia (Atmaca et al., 2004), but not

in post-traumatic stress disorder (Tezcan et al., 2003).

The study on social phobia also found a reversal of

these disturbances following 8 wk of citalopram

treatment (Atmaca et al., 2004). A study of anxious

women found reduced total antioxidant capacity

among this group compared with non-anxious

controls, in conjunction with several parameters of

impaired immune functioning (Arranz et al., 2007).

A case series has reported improvement in tricho-

tillomania, pathological nail-biting and skin-picking,

conditions that have similarities with obsessive–

compulsive disorder, using NAC (Odlaug and Grant,

2007).

Substance abuse

Substance abuse and dependence are important to

consider in psychiatric disorders, given the substantial

overlap between the two in terms of syndromal mani-

festations and causality. A solid body of literature

exists in support of the association between oxidative

stress and common drugs of abuse, including nicotine

(Petruzzelli et al., 2000), alcohol (Peng et al., 2005),

cannabis (Sarafian et al., 1999), heroin (Pan et al., 2005),

cocaine (Dietrich et al., 2005) and amphetamines (Frey

et al., 2006c). Although their precise roles are yet to be

fully understood, oxidative mechanisms have been

proposed to mediate both the processes of drug ad-

diction and toxicity (Kovacic, 2005; Kovacic and

Cooksy, 2005), and antioxidants may thus have thera-

peutic potential in the management of these condi-

tions. Preclinical evidence has indicated antioxidants

to be promising in alcohol (Amanvermez and Agara,


2006), heroin (Zhou and Kalivas, 2007) and cocaine

dependence (Baker et al., 2003). Pilot clinical trial data

of NAC in cocaine dependence have been promising,

suggesting that craving and withdrawal symptoms

(LaRowe et al., 2006) as well as cue-evoked desire are

reduced with the administration of NAC (LaRowe

et al., 2007).

Other conditions

A growing literature has been published that cites

evidence for oxidative disturbances in autism, in-

cluding genetic polymorphisms affecting oxidative

metabolic pathways (James et al., 2006), reduced anti-

oxidant capacity (Chauhan et al., 2004; James et al.,

2004, 2006), antioxidant enzyme changes (Sogut et al.,

2003; Yorbik et al., 2002; Zoroglu et al., 2004) and en-

hanced oxidative stress biomarkers (Chauhan et al.,

2004; James et al., 2004; Ming et al., 2005; Sogut et al.,

2003; Yao et al., 2006b; Zoroglu et al., 2004). Impaired

oxidative status has also been reported for ADHD,

and a randomized, controlled trial of Pycnogenol,

a pine bark extract with potent antioxidant pro-

perties, in children diagnosed with ADHD (n=61) has

found symptomatic and biochemical improvements

(Chovanova et al., 2006; Dvorakova et al., 2006;

Trebaticka et al., 2006). On the other hand, a small

(n=24) study comparing Pycnogenol and methyl-

phenidate in adult ADHD has failed to show any ad-

vantage of either treatment over placebo (Tenenbaum

et al., 2002).

Discussion

Currently, the most robust and multi-dimensional

evidence for the pathophysiological involvement of

oxidative stress is for schizophrenia, followed by

bipolar disorder, with both having support from pre-

clinical and clinical research. The data is less extensive

for the other psychiatric disorders, but there is ac-

cumulating evidence indicating a role of oxidative

stress in their aetiopathogenesis. In summary, there is

evidence for glutathione depletion in schizophrenia;

increased lipid peroxidation in schizophrenia, bipolar

and major depressive disorders ; and reduction in

antioxidants such as albumin and bilirubin in schizo-

phrenia and major depressive disorder. Findings in

relation to NO and antioxidative enzymes in these

disorders have been less consistent. Data from mol-

ecular and genetic studies have implicated oxidative

metabolic pathways in the aetiopathogenesis of

schizophrenia, bipolar disorder and possibly an-

xiety disorders. Antipsychotics, mood stabilizers and

antidepressants have all been demonstrated to have

antioxidative effects, and some antioxidants have been

reported to be of therapeutic benefit, including vit-

amins C and E and EGb for schizophrenia, and NAC

for schizophrenia and bipolar disorder.

In the interpretation of mass data, the context and

limitations of each investigation must be borne in

mind. In view of the complexities of psychiatric con-

ditions and biological systems, and the diversity of

research areas, the collective significance of study

findings would be expected to have greater strength

than individual results. For instance, a substantial

portion of the existing evidence base is derived from

the comparison of oxidative biochemical status of

patients with controls, and such studies have yielded

apparently inconsistent results, with varying presence,

directions or combinations of disturbances in markers

of oxidant and antioxidant activities. Such variations

in cross-sectional profiles of selected oxidant/anti-

oxidant markers may merely reflect their dynamic

status in the wider oxidative biochemical system,

which in turn exists in intricate balance with other

biological pathways and systems. Moreover, psychi-

atric syndromes are aetiologically heterogeneous,

commonly chronic and multiphasic, and often over-

lapping, thus further complicating the specificity of

individual marker changes. Alternatively, it is possible

that the mixed findings may signify an indirect

pathophysiological role of the relevant oxidative

markers in the disorders. However, on balance, the

literature as a whole seems to provide sufficient con-

sistent evidence that oxidative stress balance is sig-

nificantly altered in patient groups. In particular,

findings of elevated oxidative products across dis-

orders supply fairly direct evidence of increased

oxidative stress, while its aetiological significance is

supported by genetic and molecular studies that link

specific oxidative pathway polymorphisms or gene

expression to specific disorders. Genetic manipulation

experiments demonstrating positive correlations be-

tween the expression of specific oxidative genes

and anxiety behaviours in animal models further

validate this aetiopathogenic hypothesis. However, it

is difficult to distinguish from current data whether

oxidative stress results from primary excessive mito-

chondrial energy generation, primary dysfunction

within oxidative homeostatic mechanisms, or both.

Impaired mitochondrial energy metabolism has also

been suggested to be a fundamental defect in bipolar

disorder (Kato, 2007; Young, 2007), with hypometa-

bolism, energy imbalance and oxidative stress assum-

ing secondary roles, and may present an alternative

hypothesis. In practical terms, pharmacological and

866 F. Ng et al.

clinical studies have established the antioxidant

properties of efficacious pharmacotherapies, and anti-

oxidant treatment data, although limited in quantity,

have reported promising therapeutic potentials.

The implications of the expanding data on oxidative

stress mechanisms in psychiatric disorders are two-

fold, having salience in both furthering their aetio-

pathogenic understanding and treatment options.

In relation to the former, the aetiopathogenic mech-

anisms for psychiatric disorders remain largely elus-

ive, despite the growth of hypotheses on multiple

conceptual levels that include sociocultural systems,

personality, cognitive schemata, behavioural learning,

neuroanatomy, psychoneuroendoimmunology, bio-

molecules and genetics. Given the complexities of

human psychobehavioural systems and the infinite

deterministic variability behind their manifestations,

basic biopathway pathologies may present tangible

and widely applicable pathophysiological models, as

all psychobehavioural manifestations must have fun-

damental biological underpinnings. There is gathering

evidence for oxidative stress to be one such biopath-

way, as oxidative damage is believed to be a major

mechanism underlying cell dysfunction and death

in both ageing and disease processes, although its

temporal role in and relative contribution to these

processes is likely to vary. Theoretically, oxidative

stress may result from the overproduction of free

radicals, defective oxidative homeostasis, or a combi-

nation of both. Each of these situations, in turn, is

likely to stem from different causes, which may in-

clude overactive oxidative metabolism driven by

physiological stress, pathogens or the inflammatory

response, genetic polymorphisms and physiological

factors that undermine the oxidative defence capacity

of the individual, and differential expression of mito-

chondrial and metabolic enzymes. Once established,

secondary amplifications or self-perpetuating oxidat-

ive cascades may also play a role in the pathogenesis

of illnesses, the continuation of symptoms and vul-

nerability to future illness relapses.

Evidence for the interdependent relationships be-

tween oxidative pathways and those involving neuro-

transmitters, hormones and inflammatory mediators

further enhance the plausibility of the oxidative stress

hypothesis, and provide a unifying framework for

the various conceptual theories of causality. Dopa-

minergic, noradrenergic and glutamatergic over-

activity have been demonstrated to induce cytotoxicity

via oxidative stress among other mechanisms (Chan

et al., 2007; Chen et al., 2003; Penugonda et al., 2005),

and this cytotoxicity has been suggested to be specific

for neurones (Chan et al., 2007). There is also evidence

for a link between neuro-inflammatory processes and

oxidative stress, which may be mediated by the over-

production of free radicals by activated glial cells

during inflammatory states, and/or via the activation

of the cyclooxygenase (COX) and lipoxygenase (LOX)

pathways or pro-inflammatory cytokines such as

tumour necrosis factor-a (TNF-a), interleukin-1 and

interferon-c (Hayley et al., 2005; Tansey et al., 2007).

These connections provide a basis for explaining

phenomena such as drug-induced and organic psy-

chiatric syndromes, as well as comorbid somatic and

psychiatric disorders. The association of particular

neurochemical pathways with oxidative stress induc-

tion, combined with the differing vulnerabilities of

neuronal and glial cells to oxidative damage according

to their types and anatomical positions, may help to

explain the involvement of specific neurological sites

in psychiatric syndromes. This specificity of site can be

observed in neuroimaging studies (Ettinger et al.,

2007; Sheline et al., 2003; van Erp et al., 2004), and

may be useful in attempting to understand both

the acute and long-term syndromal manifestations

of the various psychiatric conditions. The involvement

of similar sites across conditions may also account

for their symptomatic overlap and diagnostic muta-

bility.

Apart from conceptual utility, a theory of value

should also demonstrate practical applicability. An

appealing aspect of the oxidative stress theory is that

regardless of the precise defect(s), this state of dis-

equilibrium can theoretically be corrected by bolster-

ing the total antioxidant capacity, providing that the

supplementary antioxidants are bioactive and able to

access the brain. The practical utility of this theory has

already garnered support from the existing literature,

which has found benefits from the use of vitamins C

and E, EGb, NAC and other antioxidants in psychiatric

disorders. NAC, in particular, seems to hold the most

promising evidence for efficacy across diagnoses, with

benefits recently reported for schizophrenia, bipolar

disorder, cocaine dependence, and impulsive control

disorders. This may relate to its bioavailability and

putative mechanisms of replenishing and enhancing

glutathione stores (Dean et al., 2004), which possibly

has a more weighted impact in the brain than other

antioxidants. Further clinical evidence is required to

consolidate the efficacies of antioxidants for the vari-

ous conditions, but their potential in acute and main-

tenance treatment settings are clearly implied on

theoretical grounds. Furthermore, these treatments

may be useful in the prevention of long-term sequelae

by minimizing cell damage and cell death, as well

as primary prevention in vulnerable individuals.


These treatments are generally associated with low

occurrence of side-effects, which is an attractive fea-

ture conducive to long-term treatment adherence.

The investigation of antioxidants in psychiatric

disorders has perhaps been hampered by several un-

favourable factors, the main ones probably relating

to the conventional aetiopathophysiological under-

standing of psychiatric disorders and to misconcep-

tions about antioxidants. Traditionally, psychiatric

teachings and research have focused on neuro-

transmitter aetiological theories, such as the dopamine

theory for schizophrenia and the monoamine hypoth-

esis for depression, and these have provided a basis

for therapeutic manipulations. Entwined with this

situation is the fact that the majority of established

biological treatments, where their mechanisms of ac-

tion are clarified, have primary discernible effects on

neurotransmitter receptors and/or their biodegra-

dation. Antioxidants serve a buffering role in oxidative

physiology, and are often regarded as ‘natural ’ rem-

edies rather than pharmacological therapies. How-

ever, the usefulness of precursor compounds to

‘natural ’ endogenous substances is not unfamiliar in

medicine, as exemplified by L-dopa in the treatment of

Parkinson disease, a drug which can be analogously

compared with the cysteine precursor, NAC. The un-

familiar mechanisms of action of antioxidants to clini-

cal psychiatry may thus have contributed to their

peripheral therapeutic status. Furthermore, the hetero-

geneity within antioxidants as a class is not widely

appreciated. Differences exist among the antioxidants

in their targets of action, as well as in their pharma-

cokinetic properties. Vitamin E, for example, has a

principal antioxidant action of scavenging peroxyl

radicals in biological lipid phases (Traber and

Atkinson, 2007), in addition to multiple non-

antioxidant properties that include modulation of

signal transduction, transcriptional and translational

processes (Zingg and Azzi, 2004), yet its antioxidant

efficacy in pathological redox states has not been

established (Azzi, 2007). Vitamin C, on the other

hand, is a scavenger of free radicals in water phases

(Rodrigo et al., 2007), while Ginkgo biloba has anti-

oxidant properties that probably include the preven-

tion of lipid peroxidation (Drieu et al., 2000). The

specific antioxidant actions of these agents, when

applied to neuropsychiatric conditions where the

precise oxidative defects are not yet clear, may account

for some inefficacious trial findings (Boothby and

Doering, 2005). In this respect, glutathione may be the

most generic of cellular antioxidants in terms of its

molecular actions, which may explain the promising

findings with NAC.

Besides pharmacological treatments, lifestyle and

dietary manipulations are relevant in optimizing oxi-

dative balance. A diet rich in natural antioxidants and

the avoidance of oxidative stress-inducing habits such

as cigarette smoking and substance abuse are prudent

measures. Diets high in saturated fats may increase

oxidative stress (Shih et al., 2007), and their intake are

best minimized. Physical exercise, specifically endur-

ance training, has also been suggested to have a ben-

eficial impact on oxidative stress status, possibly

mediated by increasing total antioxidant capacity and

GSH-Px activity (Fatouros et al., 2004).

The other major practical implication ensuing

from the oxidative stress theory of pathogenesis is the

potential use of oxidative/antioxidant profiles and

oxidative products as biomarkers of psychiatric dis-

orders, their activity status and treatment response.

Although the current state of evidence is not yet ma-

ture enough to adopt this in clinical practice, findings

of syndrome- (Reddy et al., 2003) and phase-specific

(Andreazza et al., 2007) profiles, and treatment-related

normalization (Bilici et al., 2001; Dakhale et al., 2004;

Frey et al., 2007; Gergerlioglu et al., 2007; Henneman

and Altschule, 1951; Herken et al., 2007; Khanzode

et al., 2003; Ozcan et al., 2004; Zhang et al., 2003)

support this as a possible future application. Genetic

polymorphisms of antioxidant enzymes, associated

with psychiatric disorders (Akyol et al., 2005; Saadat

et al., 2007; Tosic et al., 2006), may have potential in

assisting the identification of at-risk individuals.

In research, broad areas remain to be explored on

both preclinical and clinical levels, especially for mood

and anxiety disorders which have an early evidence

base. The use of antioxidants in their treatment is both

substantiated and promising, in view of the internally

consistent theoretical framework, convincing early

evidence, wide-ranging potential therapeutic benefits,

the high population prevalence and overall disease

burden associated with these disorders, and the lim-

ited efficacies of existing pharmacotherapies.

Acknowledgements

None.

Statement of Interest

None.

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